DESCRIPTION: (provided by the applicant) Even with current aggressive therapies, that include surgery, radiotherapy and chemotherapy, most patients with malignant glioma (MG) survive less than two years, demonstrating the need for novel, alternative therapies. Adoptive immunotherapy uses T-cells that have been genetically modified to express an MG-specific, chimeric antigen receptor (CAR) that recognizes a cell-surface protein expressed by the glioma cells. These T-cells can migrate through the brain, and are able to recognize, target and kill the malignant cells. According to th applicant, both preclinical and clinical studies have demonstrated that CAR+ T-cells that specifically recognize the MG-associated antigen, IL13Ra2, can be generated from MG patients, and successfully used to target their glioma cells which express this receptor. However, in Phase 1 clinical trials, MG tumors did recur and the genetically modified T-cells did not persist in the tumor microenvironment. Therefore, a new manufacturing platform has been developed to generate better optimized IL13Ra2-specific CAR+ T-cells that have improved persistence, and mediate superior antitumor efficacy in mouse models. The objective of this proposal is to assess the feasibility and safety of administering these optimized IL13Ra2-specific CAR+ T-cells intratumorally into human patients who have recurrent MG. Mixed CD4+ and CD8+ T-cells will be isolated from each patient and genetically modified to express the IL13Ra2-specific CAR. These cells will then be administered directly back into the tumor or tumor resection cavity of each patient, whichever is applicable. The specific aims of the study are: Aim 1: To assess the feasibility and safety, and to determine the recommended Phase 2 dose plan for the intratumoral/intracavitary administration of optimized IL13Ra2-specific CAR+ T-cells in patients with recurrent MG; and Aim 2: To evaluate surrogate indicators of in vivo effector function of the optimized IL13R?specific CAR+ T cells after transfer.